Sepsis,defined as life-threatening organ failure caused by a dysregulated host response to severe infection,is a major cause of death among intensive care unit patients.Therapies targeting on immunomodulatory is a new...Sepsis,defined as life-threatening organ failure caused by a dysregulated host response to severe infection,is a major cause of death among intensive care unit patients.Therapies targeting on immunomodulatory is a new research field in sepsis treatment.B-and T-lymphocyte attenuator(BTLA)is an inhibitory costimulatory factor molecule of B and T lymphocytes.Studies have shown that elevated expression of BTLA in lymphocytes can reduce mortality in sepsis,but its regulatory compounds and the underlying mechanism remains to be elucidated.Here,we show that treatment with CP-673451 significantly decreases mortality of septic mouse.CP-673451 is a PDGFR kinase inhibitor which can promote the expression of BTLA,inhibit the release of chemokines such as CXCL13,and reduce first the chemotaxis of B cells to the peripheral blood and vital organs.CP-673451 also inhibits both the release of cytokines and chemokines such as IL-1β,IL-6,IL-10,TNF-α,CCL1,CCL2 and CCL7 and reduces both the chemotactic ability of T cells.This suggests that CP-673451 may prevent septic death by inhibiting lymphocyte chemotaxis and alleviating“cytokine storm”.In conclusion,our study provides a new therapeutic target and an effective compound for sepsis treatment.展开更多
基金supported by the National Natural Science Foundation of China(82020108021)the Chongqing Special Project for Academicians(cstc2020yszx-jcyj X0004)+3 种基金the Project of the TraumaBurns and Combined Injury State Key Laboratory(SKLYQ201901,SKLKF201802)the Training Plan of the Innovation Ability of Military Medical Frontier Research(2019CXJSB014,2019CXJSB004)the Project of the Science and Technology Fund of Guizhou Provincial Department of Health(gzwjkj2020-1-106)。
文摘Sepsis,defined as life-threatening organ failure caused by a dysregulated host response to severe infection,is a major cause of death among intensive care unit patients.Therapies targeting on immunomodulatory is a new research field in sepsis treatment.B-and T-lymphocyte attenuator(BTLA)is an inhibitory costimulatory factor molecule of B and T lymphocytes.Studies have shown that elevated expression of BTLA in lymphocytes can reduce mortality in sepsis,but its regulatory compounds and the underlying mechanism remains to be elucidated.Here,we show that treatment with CP-673451 significantly decreases mortality of septic mouse.CP-673451 is a PDGFR kinase inhibitor which can promote the expression of BTLA,inhibit the release of chemokines such as CXCL13,and reduce first the chemotaxis of B cells to the peripheral blood and vital organs.CP-673451 also inhibits both the release of cytokines and chemokines such as IL-1β,IL-6,IL-10,TNF-α,CCL1,CCL2 and CCL7 and reduces both the chemotactic ability of T cells.This suggests that CP-673451 may prevent septic death by inhibiting lymphocyte chemotaxis and alleviating“cytokine storm”.In conclusion,our study provides a new therapeutic target and an effective compound for sepsis treatment.
